Preparation of chiral amides and amines

ABSTRACT

This invention provides a convenient method for converting oximes into enamides. The process does not require the use of metallic reagents. Accordingly, it produces the desired compounds without the concomitant production of a large volume of metallic waste. The enamides are useful precursors to amides and amines. The invention provides a process to convert a prochiral enamide into the corresponding chiral amide. In an exemplary process, a chiral amino center is introduced during hydrogenation through the use of a chiral hydrogenation catalyst. In selected embodiments, the invention provides methods of preparing amides and amines that include the 1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or 1,2,3,4-tetrahydro-1-naphthalenamine substructure.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase Application ofPCT/US2007/065659 filed Mar. 30, 2007 and claims priority under 35U.S.C. §119(e) to U.S. Provisional Patent Application No. 60/787,837filed Mar. 31, 2006, which applications are incorporated herein byreference in their entirety for all purposes.

FIELD OF THE INVENTION

This invention relates to processes suitable for the large-scalepreparation of enantiomerically- or diastereomerically-enriched chiralamides and amines prepared by these processes.

BACKGROUND OF THE INVENTION

Enantiomerically-enriched chiral primary amines are commonly used asresolving agents for racemic acids, as chiral auxiliaries for asymmetricsyntheses and as ligands for transition metal catalysts used inasymmetric catalysis. In addition, many pharmaceuticals, such assertraline, contain chiral amine moieties. Effective methods for thepreparation of such compounds are of great interest to thepharmaceutical industry. Particularly valuable are processes that allowfor the preparation of each enantiomer or diastereomer, in enantiomericor diastereomeric excess, as appropriate, from prochiral or chiralstarting materials.

Methods are available for the preparation of enantiomerically enrichedamines. For example, the addition of organometallic reagents to iminesor their derivatives is reported by Watanabe et al., Tetrahedron Asymm.(1995) 6:1531; Denmark et al., J. Am. Chem. Soc. (1987) 109:2224;Takahashi et al., Chem. Pharm. Bull. (1982) 30:3160; and the addition oforganometallic reagents to chiral oxazolidines is disclosed byMokhallalatiet et al., Tetrahedron Lett. (1994) 35:4267. Although someof these methods are widely employed, few are amenable to large-scaleproduction of amines.

Other approaches involve optical resolution of a single enantiomer ordiastereomer from a mixture. Resolution may be conducted throughstereoselective biotransformation or by the formation of diastereomericsalts that are separated by crystallization. The utility andapplicability of resolution methods relying on selectiverecrystallization are often limited by the lack of availability ofappropriate chiral auxiliaries. In addition, resolution processes uponracemic mixtures afford a maximum yield of 50% for either stereoisomer.Therefore, the resolution of racemic mixtures is generally viewed as aninefficient process.

The preparation of an enantiomerically-enriched amine via conversion ofa precursor oxime to the corresponding enamide, which is subsequentlyconverted to the amine through asymmetric hydrogenation anddeprotection, has been described (WO 99/18065 to Johnson et al.). Theprocesses are, however, not of general applicability to a wide range ofsubstrates. Moreover, many of the recognized processes require a largeexcess of metallic reagent to effect the conversion. The result is thegeneration of significant amounts of solid metal waste, a trait that isundesirable for large-scale production processes.

Therefore, a cost-efficient, scalable method for the conversion ofoximes to corresponding enamides, which does not rely on a metallicreagent, is needed. The facile, high yield conversion of readilyaccessible oximes to the corresponding enamides without the use ofmetallic reagents would be a valuable step towards the large-scalesynthesis of chiral amides and amines. The current invention addressesthis and other needs.

SUMMARY OF THE INVENTION

The present invention provides an efficient and convenient method forthe conversion of an oxime to the corresponding enamide. The method ofthe invention accomplishes the desired conversion without the use of ametallic reagent. The method is appropriate for large-scale synthesis ofenamides, amides, amines, and their derivatives.

Thus, in a first aspect, the current invention provides a method forconverting an oxime into an enamide. The method includes contacting theoxime with a phosphine and an acyl donor, under conditions appropriateto convert the oxime into the enamide. The method produces enamides inhigh yields and is generally applicable across a wide range of oximestructures. The enamides are readily converted to the correspondingamines. In an exemplary route, described in greater detail herein, theenamide is reduced to the corresponding amide, which is subsequentlydeacetylated to provide the amine.

The method is particularly useful for the large-scale synthesis ofbioactive species, such as those having the1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or1,2,3,4-tetrahydro-1-naphthalenamine substructure. Examples of bioactivecompounds with this substructure include sertraline and sertralineanalogs, and the trans isomers of sertraline, norsertraline and analogsthereof. Sertraline, (1S,4S)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, isapproved for the treatment of depression by the United States Food andDrug Administration, and is available under the trade name ZOLOFT®(Pfizer Inc., NY, N.Y., USA). In human subjects, sertraline has beenshown to be metabolized to (1S,4S)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine, also knownas desmethylsertraline or norsertraline.

Enamides provide a convenient precursor to compounds that include the1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or1,2,3,4-tetrahydro-1-naphthalenamine substructure. Accordingly, in asecond aspect, the present invention provides a method of converting anoxime having the formula:

into an enamide having the formula:

In the formulae above, the symbol R⁴ represents substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Thesymbol R⁵ represents H, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl or substituted or unsubstitutedheterocycloalkyl. The method includes contacting said oxime with aphosphine and an acyl donor under conditions appropriate to convert saidoxime to said enamide.

In a third aspect, the invention provides a mixture comprising:

In the formulae above, Q⁻ is an anion. The indices c and f areindependently selected numbers from 0 to 1. The indices x and yindependently represent (R) or (S). In an exemplary embodiment, when xis (R), y is (R) and when x is (S), y is (S). In another exemplaryembodiment, when x is (S), y is (R).

The present invention provides a general and efficient method forconverting oximes to enamides. Moreover, the invention provides a methodfor the stereo-selective synthesis of sertraline and sertraline analogs,and the trans isomers of sertraline, norsertraline and analogs thereof.Additional objects, advantages and embodiments of the present inventionare set forth in the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations

As used herein, “COD” means 1,5-cyclooctadiene.

DEFINITIONS

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents, which would result from writing thestructure from right to left, e.g., —CH₂O— is preferably intended toalso recite —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight- or branched-chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated (i.e.C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbonradicals include, but are not limited to, groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “alkyl,” unlessotherwise noted, also preferably include those derivatives of alkyldefined in more detail below, such as “heteroalkyl.” Alkyl groups thatare limited to hydrocarbon groups are termed “homoalkyl”. The term“alkyl”, as used herein refers to alkyl, alkenyl and alkynyl moieties,each of which can be mono-, di- or polyvalent species. Alkyl groups arepreferably substituted, e.g., with one or more groups referred tohereinbelow as an “alkyl group substituent.”

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight- or branched-chain, orcyclic alkyl radical consisting of the stated number of carbon atoms andat least one heteroatom selected from the group consisting of B, O, N,Si and S, wherein the heteroatom may optionally be oxidized and thenitrogen atom may optionally be quaternized. The heteroatom(s) may beplaced at any internal position of the heteroalkyl group or at aterminus of the chain, e.g., the position through which the alkyl groupis attached to the remainder of the molecule. Examples of “heteroalkyl”groups include, but are not limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Two or more heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the term“heteroalkylene” by itself or as part of another substituent refers to asubstituted or unsubstituted divalent heteroalkyl radical, asexemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxy,alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —C(O)₂R′—represents —C(O)₂R′— and, preferably, —R′C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is meant to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 to 3 rings, one or more of which is optionally acycloalkyl or heterocycloalkyl), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of aryl and heteroaryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group of “arylgroup substituents” described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) preferably includes both homoaryland heteroaryl rings as defined above. Thus, the term “arylalkyl”optionally includes those radicals in which an aryl group is attached toan alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like)including those alkyl groups in which a carbon atom (e.g., a methylenegroup) has been replaced by, for example, an oxygen atom (e.g.,phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and thelike).

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: —OR′, ═O, ═NR′, —NR′R″, —SR′,-halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″,—NR—C(NR′R″)=NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number ranging from zero to (2 m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R″′ and R″″ eachpreferably independently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, e.g., aryl substitutedwith 1-3 halogens, substituted or unsubstituted alkyl, alkoxy orthioalkoxy groups, or arylalkyl groups. When a compound of the inventionincludes more than one R group, for example, each of the R groups isindependently selected as are each R′, R″, R″′ and R″″ groups when morethan one of these groups is present. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include,but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “alkyl” includes groups with carbon atoms bound to groups otherthan hydrogen, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl(e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: halogen, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, —SiR′R″R″′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂, —R′, —N₃,—CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a numberranging from zero to the total number of open valences on the aromaticring system; and where R′, R″, R″′ and R″″ are preferably independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer from 0 to 3. Alternatively,two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—, —NR—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 4. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N),sulfur (S) and silicon (Si).

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocyclyl groups.

The term “salt(s)” includes salts of the compounds which are preparedwith relatively nontoxic acids or bases, depending on the particularsubstituents found on the compounds described herein. When compounds ofthe present invention contain relatively acidic functionalities, baseaddition salts can be obtained by contacting the neutral form of suchcompounds with a sufficient amount of the desired base, either neat orin a suitable inert solvent. Examples of base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds of the present invention containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of acid addition salts include those derived from inorganicacids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids, and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,butyric, maleic, malic, malonic, benzoic, succinic, suberic, fumaric,lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate, and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge et al., Journal of Pharmaceutical Science, 66: 1-19 (1977)).Certain specific compounds of the present invention contain both basicand acidic functionalities that allow the compounds to be converted intoeither base or acid addition salts. Hydrates of the salts are alsoincluded.

When the compound prepared by a method of the invention is apharmacological agent, the salt is preferably a pharmaceuticallyacceptable salt. Examples of pharmaceutically acceptable salts arepresented hereinabove, and are generally known in the art. See, forexample, Wermuth, C., PHARMACEUTICAL SALTS: PROPERTIES, SELECTION ANDUSE—A HANDBOOK, Verlag Helvetica Chimica Acta (2002)

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

In addition to salt forms, the present invention provides compounds thatare in a prodrug form. Prodrugs of the compounds described herein arethose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

As used herein, and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide thecompound. Examples of prodrugs include, but are not limited to,compounds that comprise biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogs. Other examples of prodrugs include compounds thatcomprise NO, NO₂, —ONO, or —ONO₂ moieties. The term “prodrug” isaccorded a meaning herein such that prodrugs do not encompass the parentcompound of the prodrug. When used to describe a compound of theinvention, the term “prodrug” may also interpreted to exclude othercompounds of the invention.

As used herein, and unless otherwise indicated, the terms“biohydrolyzable carbamate,” “biohydrolyzable carbonate,”“biohydrolyzable ureide” and “biohydrolyzable phosphate” mean acarbamate, carbonate, ureide and phosphate, respectively, of a compoundthat either: 1) does not interfere with the biological activity of thecompound but can confer upon that compound advantageous properties invivo, such as uptake, duration of action, or onset of action; or 2) isbiologically inactive but is converted in vivo to the biologicallyactive compound. Examples of biohydrolyzable carbamates include, but arenot limited to, lower alkylamines, substituted ethylenediamines,aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines,and polyether amines.

As used herein, and unless otherwise indicated, the term“biohydrolyzable ester” means an ester of a compound that either: 1)does not interfere with the biological activity of the compound but canconfer upon that compound advantageous properties in vivo, such asuptake, duration of action, or onset of action; or 2) is biologicallyinactive but is converted in vivo to the biologically active compound.Examples of biohydrolyzable esters include, but are not limited to,lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters,and choline esters.

As used herein, and unless otherwise indicated, the term“biohydrolyzable amide” means an amide of a compound that either: 1)does not interfere with the biological activity of the compound but canconfer upon that compound advantageous properties in vivo, such asuptake, duration of action, or onset of action; or 2) is biologicallyinactive but is converted in vivo to the biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention.

As used herein, and unless otherwise indicated, a composition that is“substantially free” of a compound means that the composition containsless than about 20% by weight, more preferably less than about 10% byweight, even more preferably less than about 5% by weight, and mostpreferably less than about 3% by weight of the compound.

As used herein, the term “substantially free of its cis stereoisomer”means that a mixture of a compound is made up of a significantly greaterproportion of its trans stereoisomer than of its optical antipode. In apreferred embodiment of the invention, the term “substantially free ofits cis stereoisomer” means that the compound is made up of at leastabout 90% by weight of its trans stereoisomer and about 10% by weight orless of its cis stereoisomer. In a more preferred embodiment of theinvention, the term “substantially free of its cis stereoisomer” meansthat the compound is made up of at least about 95% by weight of itstrans stereoisomer and about 5% by weight or less of its cisstereoisomer. In an even more preferred embodiment, the term“substantially free of its cis stereoisomer” means that the compound ismade up of at least about 99% by weight of its trans stereoisomer andabout 1% or less of its cis stereoisomer.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr, J.Chem. Ed., 62: 114-120 (1985): solid and broken wedges are used todenote the absolute configuration of a chiral element; wavy linesindicate disavowal of any stereochemical implication which the bond itrepresents could generate; solid and broken bold lines are geometricdescriptors indicating the relative configuration shown but not implyingany absolute stereochemistry; and wedge outlines and dotted or brokenlines denote enantiomerically pure compounds of indeterminate absoluteconfiguration.

The terms “enantiomeric excess” and “diastereomeric excess” are usedinterchangeably herein. Compounds with a single stereocenter arereferred to as being present in “enantiomeric excess.” Those with atleast two stereocenters are referred to as being present in“diastereomeric excess.”

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, e.g., tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

INTRODUCTION

The present invention provides a non-metal mediated method for theconversion of oximes to the corresponding enamides. The enamides areformed in high yields and purities, making them suitable substrates forhomogeneous asymmetric hydrogenation, a process that affordsenantiomerically-enriched amides. The amides can be deprotected tofurnish enantiomerically-enriched amines. Either enantiomer of the aminemay be obtained by this method. Ketones and aldehydes can thus betransformed into enantiomerically-enriched chiral amines. The process isamenable to large-scale production.

Methods A. Oxime to Enamide

In a first aspect, the present invention provides a method forconverting an oxime into an enamide. The method includes contacting theoxime with a phosphine and an acyl donor, under conditions appropriateto convert the oxime into the enamide. Exemplary conditions are setforth herein.

In one embodiment, the oxime of use in the method of the invention hasthe formula:

The symbols R¹, R² and R³ represent radicals that are independentlyselected from H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl. At least two of R¹, R² and R³ are optionally joined toform a ring system selected from substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl.

In another exemplary embodiment, the oxime has the formula:

The symbol Ar represents substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl. R⁴ is H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or substituted or unsubstituted heterocycloalkyl. The index ais an integer from 1 to 4.

In an exemplary embodiment according to this aspect, R⁴ is substitutedor unsubstituted aryl (e.g., phenyl). In a further exemplary embodiment,R⁴ is phenyl substituted with at least one halogen atom.

In yet another exemplary embodiment, R⁴ has the formula:

in which the symbols X¹ and X² represent independently selected halomoieties. In a preferred embodiment, X¹ and X² are each chloro.

In another exemplary embodiment, the oxime has the formula:

wherein R⁴ is selected from substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl.

In a further exemplary embodiment, the oxime has the formula:

The preparation of oximes is well known in the art and a wide range ofmethods is known and readily practiced by those of skill in the art.Typically, oximes are prepared by reaction of ketones or aldehydes withhydroxylamine (or alkyloxyamine) under one of a variety of conditions.See, e.g., Sandler and Karo, “ORGANIC FUNCTIONAL GROUP PREPARATIONS,”Vol. 3, pp 372-381, Academic Press, New York, 1972.

In an exemplary embodiment, optically pure tetralone is converted intothe corresponding oxime according to Scheme 1.

In Scheme 1, optically pure tetralone 1 is treated with hydroxylaminehydrochloride, and sodium acetate in methanol to afford the oxime 2.Compound 2 can either be isolated or carried forward as a solution in asuitable solvent to the next step. In another method, a ketone isconverted to the corresponding oxime in an aromatic hydrocarbon solvent,e.g., toluene.

According to the process of the invention, the oxime is converted intoan enamide. In an exemplary embodiment, the enamide has the formula:

in which R¹-R³ are as discussed above and R⁵ is selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.

In another exemplary embodiment, the enamide has the formula:

in which R⁴ is selected from substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. R⁵ is selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.

An exemplary enamide has the formula:

In an exemplary embodiment according to this aspect, C-4 of the ketone,oxime and enamide is of (S)-configuration.

In a preferred embodiment, the enamide has the formula:

C-4 has a configuration selected from (R) and (S) and, in a preferredembodiment, C-4 is of (S)-configuration. In another embodiment, themethod provides an enamide mixture including both (S)- and(R)-enantiomers.

Acyl Donor

Acyl donors of essentially any structure are of use in the presentinvention. An exemplary acyl donor has the formula:

Z—C(O)—R⁵

in which Z is a leaving group. R⁵ is a member selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.

In an exemplary embodiment, the acyl donor is an acid anhydride, inwhich Z has the formula:

R⁶—C(O)—O—

in which R⁶ is a member selected from substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl andsubstituted or unsubstituted heterocycloalkyl.

In another exemplary embodiment, R⁵ and R⁶ are independently selectedsubstituted or unsubstituted C₁-C₄ moieties.

In another embodiment, the acyl donor is an anhydride, preferably aceticanhydride (Ac₂O).

In another exemplary embodiment, the acyl donor is a member selectedfrom an acid chloride (Z═Cl) and an activated ester, e.g., an N-hydroxysuccinimidyl ester.

The acyl donor can be present in any useful amount and selection of thisamount is within the abilities of those of skill in the art. In anexemplary embodiment, the acyl donor is used in an amount from about 1to about 3 equivalents, preferably from about 1 to about 2 equivalentsand, more preferably, from about 1 to about 1.5 equivalents relative tothe oxime substrate.

Phosphine

Phosphorus reagents, such as phosphines, of any structure are of use inpracticing the present invention. For example, in general, phosphineshave the formula:

P(Q)₃

in which each Q is independently selected from H, substituted orunsubstituted alkyl and substituted or unsubstituted aryl.

In an exemplary embodiment, each Q is a member independently selectedfrom substituted or unsubstituted C₁-C₆ alkyl and substituted orunsubstituted phenyl. Presently preferred phosphorus reagents include,but are not limited to, diphenylphosphine (Ph₂PH), triphenylphosphine(Ph₃P), tri-n-butylphosphine (n-Bu₃P), triethylphosphine (Et₃P),tri-n-propylphosphine (n-Pr₃P), 1,2-bisdiphenylphosphinoethane(Ph₂PCH₂CH₂PPh₂), diethyl phosphite (Et₂OP(O)H), triphenyl phosphite((PhO)₃P), P-chlorodiphenylphosphine (Ph₂PCl),methyltriphenylphosphonium bromide (MePh₃PBr), andbenzyltriphenylphosphonium chloride (BnPh₃PCl).

The phosphorus reagent, such as phosphine, is incorporated into thereaction mixture in substantially any useful amount. Exemplary reactionsof the invention utilize from about 0.5 equivalents to about 5equivalents, preferably from about 1 equivalent to about 3 equivalentsand, more preferably, from about 1.1 equivalents to about 2 equivalentsof the phosphorus reagent with respect to the carbonyl-containingsubstrate.

Solvent

In an exemplary embodiment, the oxime is contacted with the phosphorusreagents (e.g., phosphine) and the acyl donor in the presence of anorganic solvent. The solvent can be a protic or an aprotic solvent. In apreferred embodiment, the solvent is an aprotic solvent. In a furtherpreferred embodiment, the aprotic solvent is an aromatic solvent (e.g.,toluene, xylene and combinations thereof).

In an exemplary embodiment, in which the oxime is compound 3, thesolvent is preferably toluene.

B. Enamide to Amide

In another aspect, the current invention provides a method forconverting an enamide to an amide. The method includes, contacting theenamide with a hydrogenation catalyst and hydrogen or a hydrogentransfer reagent under conditions appropriate to hydrogenate acarbon-carbon double bond of the enamide, thereby converting the enamideto an amide.

The methods of the present invention are not limited to practice onenamides characterized by any particular structural element ormembership within any single structural class. The methods disclosedherein are of broad applicability across a wide range of enamidestructures. Exemplary reagents and reaction conditions for theconversion of the enamide to the amide are set forth below.

Catalyst

The carbon-carbon double bonds of the enamides are reduced by processessuch as hydrogen transfer, in which a hydrogen-donor such as a secondaryalcohol, and in particular isopropanol is used; and hydrogenation, inwhich molecular hydrogen is used. Both hydrogen transfer andhydrogenation processes require a catalyst or catalytic system toactivate the reducing agent, namely an alcohol or molecular hydrogen,respectively.

In selected embodiments of the present invention, the enamide substrateis chiral or prochiral and the reduction, hydrogen transfer orhydrogenation is performed in a stereoselective manner. In thisembodiment, it is generally preferred that the catalyst is a chiralcatalyst. Also preferred is that the chiral catalyst is a transitionmetal catalyst.

Numerous reports have been published on chiral transition metal complexcatalysts usable in catalytic asymmetric hydrogenation reactions. Amongthese, transition metal complexes of ruthenium, iridium, rhodium,palladium, nickel or the like, which contain optically active phosphinesas ligands, have been reported to exhibit excellent performance ascatalysts for asymmetric synthetic reactions, and some of them arealready used in industrial application. See, e.g., ASYMMETRIC CATALYSISIN ORGANIC SYNTHESIS, Ed., R. Noyori, Wiley & Sons (1994); and G.Franciò, et al., Angewandte Chemie. Int. Ed., 39: 1428-1430 (2000).

In a preferred embodiment, the metal in the catalyst is rhodium (Rh),ruthenium (Ru) or iridium (Ir).

In an exemplary embodiment, the hydrogenation catalyst used in thepresent methods is a chiral complex of a transition metal with a chiralphosphine ligand, including monodentate and bidentate ligands. Forexample, preferred bidentate ligands include1,2-bis(2,5-dimethylphospholano)ethane (MeBPE),P,P-1,2-phenylenebis{(2,5-endo-dimethyl)-7-phosphabicyclo[2.2.1]heptane}(MePennPhos), 5,6-bis(diphenylphosphino) bicyclo[2.2.1]hept-2-ene(NorPhos) and 3,4-bis(diphenylphosphino)N-benzyl pyrrolidine(commercially available as catASium® D).

In a preferred embodiment for making the amide derived from tetralones,the chiral catalyst is (R,S,R,S)-MePennPhos(COD)RhBF₄,(R,R)-MeBPE(COD)RhBF₄, (R,R)—NorPhos(COD)RhBF₄ (Brunner et al.,Angewandte Chemie 91(8): 655-6 (1979)), or (R,R)-catASium® D(COD)RhBF₄(Nagel et al., Chemische Berichte 119(11): 3326-43 (1986)).

The catalyst is present in the reaction mixture in any useful amount.Determining an appropriate catalyst structure and an effective amount ofthis catalyst is well within the abilities of those skilled in the art.In an exemplary embodiment, the catalyst is present in an amount of fromabout 0.005 mol % to about 1 mol % Generally, it is preferred that thecatalyst be present in an amount of from about 0.01 mol % to about 0.5mol % and, even more preferably, from about 0.02 mol % to about 0.2 mol%.

In an exemplary embodiment, the enamide is hydrogenated to thecorresponding amide in the presence of from about 0.02 to about 0.3 mol%, preferably, from about 0.03 to about 0.2 mol %, and even morepreferably, from about 0.03 to about 0.1 mol % Rh-MeBPE catalyst.

In another exemplary embodiment, the enamide is hydrogenated to give theamide in the presence of about 0.1 to about 1.0 mol %, preferably about0.1 to about 0.5 mol % and, more preferably about 0.3 mol % of aRh-PennPhos catalyst.

In another exemplary embodiment, the enamide is hydrogenated to give theamide in the presence of about 0.005 to about 1.0 mol %, preferablyabout 0.01 to about 0.5 mol % and, more preferably about 0.02 to about0.1 mol % of (R,R)-NorPhos(COD)RhBF₄ catalyst.

A presently preferred catalyst of use in the invention provides theamide in a high yield of at least 85%, preferably at least 90% and morepreferably at least 95% yield from the enamide. A generally preferredcatalyst is one that provides high yields of amides when the synthesisis on a large scale of at least 300 grams, preferably at least 500grams, more preferably at least 750 grams and even still more preferablyat least 1,000 g. Preferred catalysts provide the amides in the highyield set forth above when the reaction is carried out on the largescale, also set forth above. An exemplary catalyst having thesedesirable properties is (R,R)-NorPhos(COD)RhBF₄.

Hydrogen Pressure

When the conversion of the C—C double bond of the enamide to thecorresponding C—C single bond is effected by hydrogenation, the pressureof the hydrogen in the reaction vessel can be adjusted to optimize thereaction yield and stereoselectivity. The methods of the invention arepracticed with any useful hydrogen pressure, and those with skill in theart will understand how to adjust the hydrogen pressure to optimize thedesired result.

In an exemplary embodiment, the enamide is hydrogenated, to afford theamide, at a hydrogen pressure of about 2 to about 10 bar, preferablyabout 4 to about 8 bar and, more preferably, about 5 to about 6 bar.

Solvent

The methods of the invention are not limited to practice with any onesolvent or any class of solvents, e.g. protic, aprotic, aromatic, oraliphatic. Choice of an appropriate solvent for a particular reaction iswell within the abilities of those of skill in the art.

In an exemplary embodiment, the enamide is converted to the amide in thepresence of a solvent, which is a protic solvent, an aprotic solvent, ora mixture thereof. In a preferred embodiment the solvent is a proticsolvent, which is an alcohol, more preferably, a C₁ to C₄-alcohol. Inother preferred embodiments, the alcohol is methanol, ethanol,n-propanol, iso-propanol, n-butanol, 2-butanol, or2,2,2-trifluoroethanol (CF₃CH₂OH). In a presently preferred embodiment,the alcohol is iso-propanol.

In another exemplary embodiment, the aprotic solvent is an aromaticsolvent, a non-aromatic solvent or a mixture thereof. Exemplary aromaticsolvents of use in the present invention include toluene, benzene, andxylene, and preferably less toxic aromatic solvents such as toluene andxylene. Exemplary non-aromatic solvents of use in the methods of theinvention include tetrahydrofuran (THF), dichloromethane (CH₂Cl₂), ethylacetate (EtOAc), and acetonitrile (CH₃CN).

The solvent and substrate are present in essentially any useful ratio.In an exemplary embodiment, the solvent and substrate are present inamounts that provide a substrate solution of from about 0.05 M to about0.5 M, preferably, from about 0.1 M to about 0.3 M and, more preferably,from about 0.12 M to about 0.34 M.

Amide

The amides formed by the methods of the invention have diversestructures and can include alkyl, heteroalkyl, aryl and heteroarylsubstructures. In an exemplary embodiment, the amide has the formula:

in which R¹-R³ and R⁵ are as discussed above.

As discussed previously, the methods of the invention are useful forpreparing amides that include within their structure the1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or1,2,3,4-tetrahydro-1-naphthalenamine substructure. Thus, in an exemplaryembodiment, the amide has the formula:

in which R⁴ and R⁵ are as described above.

An exemplary amide is a trans amide, having the formula:

A further exemplary amide has the formula:

In a preferred embodiment, the amide has the formula:

In each of the amide formulae above, C-1 and C-4 have a configurationindependently selected from (R) and (S), and in a preferred embodiment,C-1 is of (R)-configuration, and C-4 is of (S)-configuration.

Enantiomeric or Diastereomeric Excess

In a preferred embodiment, the enantiomeric excess (ee) of a desiredenantiomer or the diastereomeric excess (de) of a desired diastereomerproduced by the present method is from about 60% ee/de to about 99%ee/de, preferably from about 70% ee/de to about 99% ee/de, morepreferably, from about 80% ee/de to about 99% ee/de, still morepreferably, from about 90% cc/de to about 99% ee/de.

In another preferred embodiment, the invention provides an amide havingan enantiomeric or diastereomeric excess of at least about 99%,preferably, at least about 99.4% and, more preferably, at least about99.8%. Amides that are essentially free of their optical antipodes areaccessible through the methods of the invention.

When using rhodium catalyst systems based on chiral bidentate ligands,such as those derived from 1,2-bis(phospholano)ethane (BPE) ligands,P,P-1,2-phenylenebis(7-phosphabicyclo[2.2.1]heptane) (PennPhos) ligands,5,6-bis(phosphino)bicyclo[2.2.1]hept-2-ene (NorPhos) ligands, or3,4-bis(phosphino) pyrrolidine (commercially available as catASium® D)ligands, the diastereomeric purity of the trans amide derived from thecorresponding enamide is surprisingly high.

In a preferred embodiment, when the amide includes the1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or1,2,3,4-tetrahydro-1-naphthalenamine subunit, the method provides(1R,4S)-trans amide, which is substantially free of its cis isomer.

In one exemplary embodiment, the enamide is hydrogenated at about 4 toabout 6 bar hydrogen pressure using about 0.03 to about 0.05 mol % of aRh-Me-BPE catalyst in isopropanol, to give the trans N-acetyl amide inabout 80 to about 99% de, preferably at least 95% de, and morepreferably at least 99% de.

In another exemplary embodiment, the enamide is hydrogenated at about 4to about 5 bar hydrogen pressure, using about 0.2 to about 0.5 mol % ofa Rh-PennPhos catalyst in isopropanol, to give the trans N-acetyl amidein about 80 to about 99% de, preferably at least 95% de, and morepreferably at least 99% de.

In yet another exemplary embodiment the enamide is hydrogenated at about5 to about 8 bar hydrogen pressure, using about 0.01 to about 0.05 mol %of (R,R)NorPhos(COD)RhBF₄ catalyst in isopropanol to give the transN-acetyl amide in about 80-99% de, preferably at least 95% de, and morepreferably at least 99% de.

In a preferred embodiment, the hydrogenation is carried out at anenamide concentration of about 0.1 M to about 0.3 M.

In a further exemplary embodiment, the stereoisomerically enriched amideis purified, or further enriched, by selective crystallization. Inanother exemplary embodiment, the amide is purified, or enriched, to anenantiomeric or diastereomeric purity of about 90 to about 99% ee/de. Inanother exemplary embodiment, the amide is purified, or enriched, to anenantiomeric or diastereomeric purity of about 95 to about 99% ee/de.

The product of the hydrogenation or hydrogen transfer can beenantiomerically or diastereomerically enriched by methods known in theart, e.g., chiral chromatography, selective crystallization and thelike. It is generally preferred that the enrichment afford a product atleast about 95% of which is a single stereoisomer. More preferably, atleast about 97%, still more preferably at least about 99% is a singlestereoisomer.

In a presently preferred embodiment, the enriched trans amide ispurified, or enriched, by selective crystallization, affording thedesired trans isomer in about 99% de.

C. Amide to Amine

In another aspect, the current invention provides methods for convertingan amide formed from the corresponding enamide to an amine. In anexemplary embodiment, the method includes contacting the amide with adeacylating reagent under conditions appropriate to deacylate the amide,thereby forming an amine.

In an exemplary embodiment, the amine has the formula:

or a salt thereof. The radicals have the identities set forth above.

The amine can be of any desired structure, however, it is preferably achiral amine. When the amine is chiral, the enantiomeric excess (ee) ofa desired enantiomer or the diastereomeric excess (de) of a desireddiastereomer produced by the present method is from about 60% ee/de toabout 99% ee/de, preferably from about 70% ee/de to about 99% ee/de,more preferably, from about 80% ee/de to about 99% cc/de, still morepreferably, from about 90% cc/de to about 99% cc/de.

In another preferred embodiment, the invention provides an amine havingan enantiomeric or diastereomeric excess of at least about 99%,preferably, at least about 99.4% and, more preferably, at least about99.8%. Amines that are essentially free of their optical antipodes areaccessible through the methods of the invention.

In an exemplary embodiment, the amine includes the1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or1,2,3,4-tetrahydro-1-naphthalenamine substructure, and has the formula:

or a salt thereof.

In a preferred embodiment, the amine is a trans amine, having theformula:

or a salt thereof.

An exemplary amine has the formula:

in which Q⁻ is an anion. The index e is a number from 0 to 1. The indexmay take a fractional value, indicating that the amine salt is ahemi-salt.

In a preferred embodiment, the amine has the formula:

wherein Q⁻ and e are as described above.

C-1 and C-4 have a configuration independently selected from (R) and(S). Preferably C-1 is of (R)-configuration, and C-4 is of(S)-configuration.

In another preferred embodiment, the amine is in the trans configurationand is substantially free of the cis isomer.

The amide is deacylated by any suitable process. Many methods ofdeacylating amides to the corresponding amines are known in the art. Inan exemplary embodiment, the deacylating reagent is an enzyme. Exemplaryenzymes of use in this process include those of the class EC 3.5.1(e.g., amidase, aminoacylase), and EC 3.4.19.

In another embodiment, the deacylating reagent is an acid or a base. Theacid or base can be either inorganic or organic. Mixtures of acids ormixtures of bases are useful as well. When the deacylating reagent is anacid, it is generally preferred that the acid is selected so that theacid hydrolysis produces a product that is a form of the amine. In anexemplary embodiment, the acid is hydrochloric acid (HCl).

Other deacylating conditions of use in the present invention include,but are not limited to, methanesulfonic acid/HBr in alcoholic solvents,triphenylphosphite/halogen (e.g., bromine, chlorine) complex and adi-t-butyl dicarbonate/lithium hydroxide sequence.

In a preferred embodiment, the amide is deacylated by treatment with anactivating agent, e.g., trifluoromethanesulfonic anhydride, phosgene,and preferably, oxalyl chloride/pyridine. The reaction is quenched withan alcohol, preferably a glycol, e.g., propylene glycol.

When the amide includes the 1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamineor 1,2,3,4-tetrahydro-1-naphthalenamine substructure, the deacylationconditions preferably are selected such that formation of anydihydronaphthalene side products are minimized.

The amine can be isolated or enriched. A currently preferred method ofisolating or enriching the amine includes at least one step of selectivecrystallization.

The amine is optionally N-alkylated or N-acylated to prepare thecorresponding N-alkyl or N-acyl derivative.

In an exemplary embodiment, the invention provides a method suitable forthe large scale preparation of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 5 and saltforms thereof. In an exemplary embodiment, the process involves thesynthesis of an enamide, e.g. enamide 3, starting from optically pure(4S)-tetralone 1 via the oxime 2, and subjecting enamide 3 to catalyticasymmetric hydrogenation to afford amide 4, which upon N-deacylationaffords trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine 5, or a saltthereof (Scheme 2).

In a preferred embodiment, the compound prepared by the route of Scheme2 is (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine. Even morepreferred is the preparation of the compound substantially free of itscis isomer.

Compounds according to formula 5 include stereoisomers ofdesmethylsertraline. The N-methyl analog of 5 is a stereoisomer ofsertraline.

The primary clinical use of sertraline is in the treatment ofdepression. In addition, U.S. Pat. No. 4,981,870 discloses and claimsthe use of sertraline and related compounds for the treatment ofpsychoses, psoriasis, rheumatoid arthritis and inflammation.

(1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine and(1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine are usefulin the treatment of CNS-related disorders that are modulated bymonoamine activity (U.S. Patent Application No. 2004/0092605 to Jerussiet al.; cited references). Those CNS-related disorders include mooddisorders (e.g. depression), anxiety disorders (e.g., OCD), behavioraldisorders (e.g. ADD and ADHD), eating disorders, substance abusedisorders and sexual function disorders. Potentially, these moleculesproduce diminished side effects as compared to the current standards oftreatment. The compounds are also useful for the prophylaxis ofmigraine.

IV. Compositions

In another aspect, the invention provides a mixture comprising:

in which R⁴ is a member selected from substituted or unsubstituted aryland substituted or unsubstituted heteroaryl. Q⁻ is an anion. The indicesc and f independently represent a number from 0 to 1. Thus, thestructures above encompass hemi-salts.

The indices x and y are independently selected from (S) and (R). In oneembodiment, when x is (S), y is (S) and when x is (R), y is (R). Inanother embodiment, when x is (S), y is (R).

In an exemplary embodiment, R⁴ is substituted or unsubstituted aryl. Apreferred aryl moiety is a substituted or unsubstituted phenyl moiety.

In another exemplary embodiment, the mixture comprises compounds withthe following formulae:

in which e, f, x and y are as described above.

The mixtures set forth above are of use in pharmaceutical formulations.It is generally recognized that stereoisomers of bioactive compounds mayhave different properties. For example, the S-enantiomer of thebeta-adrenergic blocking agent, propranolol, is known to be 100 timesmore potent than the R-enantiomer. However, potency is not the onlyconcern in the field of pharmaceuticals. Optical purity is importantsince certain isomers may actually be deleterious rather than simplyinert. Mixtures of diastereomers effectively combine and modulate theproperties of each of the pure diastereomers. Thus, in selectedembodiments, the invention provides mixtures of diastereomeric compoundsA and B.

According to the present invention, a therapeutically effective amountof A or B, which may be a pure isomer or a mixture of any A and B, mayalso be administered to a person in need of therapy.

Disorders treatable with compounds prepared by the methods of thepresent invention include, but are not limited to, depression, majordepressive disorder, bipolar disorder, chronic fatigue disorder,seasonal affective disorder, agoraphobia, generalized anxiety disorder,phobic anxiety, obsessive compulsive disorder (OCD), panic disorder,acute stress disorder, social phobia, fibromyalgia, neuropathic pain,posttraumatic stress disorder, premenstrual syndrome, menopause,perimenopause and male menopause.

In addition to their beneficial therapeutic effects, compounds preparedby methods of the present invention may provide the additional benefitof avoiding or reducing one or more of the adverse effects associatedwith conventional mood disorder treatments. Such side effects include,for example, insomnia, breast pain, weight gain, extrapyramidalsymptoms, elevated serum prolactin levels and sexual dysfunction(including decreased libido, ejaculatory dysfunction and anorgasmia).

The compounds (and their mixtures) prepared by the methods of thepresent invention are also effective for treating disruptive behaviordisorders, such as attention deficit disorder (ADD) and attentiondeficit/hyperactivity disorder (ADHD), which is in accordance with itsaccepted meaning in the art, as provided in the DSM-IV-TR™. Thesedisorders are defined as affecting one's behavior resulting ininappropriate actions in learning and social situations. Although mostcommonly occurring during childhood, disruptive behavior disorders mayalso occur in adulthood.

The term “treating” when used in connection with the foregoing disordersmeans amelioration, prevention or relief from the symptoms and/oreffects associated with these disorders and includes the prophylacticadministration of a compound of formula A or B, a mixture thereof, or apharmaceutically acceptable salt of either, to substantially diminishthe likelihood or seriousness of the condition.

Pure compounds and mixtures prepared by the methods of the presentinvention are also effective for treating eating disorders. Eatingdisorders are defined as a disorder of one's appetite or eating habitsor of inappropriate somatotype visualization. Eating disorders include,but are not limited to, anorexia nervosa; bulimia nervosa, obesity andcachexia.

Mood disorders, such as depressive disorders, e.g., dysthymic disorderor major depressive disorder; bipolar disorders, e.g., bipolar Idisorder, bipolar II disorder, and cyclothymic disorder; mood disorderdue to a general medical condition with depressive, and/or manicfeatures; and substance-induced mood disorder can be treated usingcompounds and mixtures of the invention.

Anxiety disorders, such as acute stress disorder, agoraphobia withouthistory of panic disorder, anxiety disorder due to general medicalcondition, generalized anxiety disorder, obsessive-compulsive disorder,panic disorder with agoraphobia, panic disorder without agoraphobia,posttraumatic stress disorder, specific phobia, social phobia, andsubstance-induced anxiety disorder are treatable with compounds andmixtures of the invention.

Compounds and mixtures prepared by methods of the invention are alsoeffective for treating cerebral function disorders. The term cerebralfunction disorder, as used herein, includes cerebral function disordersinvolving intellectual deficits, and may be exemplified by seniledementia, Alzheimer's type dementia, memory loss, amnesia/amnesticsyndrome, epilepsy, disturbances of consciousness, coma, lowering ofattention, speech disorders, Parkinson's disease and autism.

The compounds and mixtures are also of use to treat schizophrenia andother psychotic disorders, such as catatonic, disorganized, paranoid,residual or differentiated schizophrenia; schizophreniform disorder;schizoaffective disorder; delusional disorder; brief psychotic disorder;shared psychotic disorder; psychotic disorder due to a general medicalcondition with delusions and/or hallucinations.

The compounds of formulae A and B are also effective for treating sexualdysfunction in both males and females. Disorders of this type include,for example, erectile dysfunction and orgasmic dysfunction related toclitoral disturbances.

Compounds and mixtures prepared by the methods of the present inventionare also useful in the treatment of substance abuse, including, forexample addiction to cocaine, heroin, nicotine, alcohol, anxiolytic andhypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens,phenylcyclidine, volatile solvents, and volatile nitrites. Nicotineaddiction includes nicotine addiction of all known forms, such as, forexample, nicotine addiction resulting from cigarette, cigar and/or pipesmoking, as well as addiction resulting from tobacco chewing. In thisrespect, due to their activity as norepinephrine and dopamine uptakeinhibitors, the compounds of the present invention can function toreduce the craving for the nicotine stimulus. Bupropion (ZYBAN®,GlaxoSmithKline, Research Triangle Park, N.C., USA) is a compound thathas activity at both norepinephrine and dopamine receptors, and iscurrently available in the United States as an aid to smoking cessationtreatment. As a benefit beyond the therapeutic activity of buproprion,however, the compounds of the present invention provide an additionalserotonergic component.

Pure compounds and mixtures prepared by the methods of the presentinvention are also effective in the prophylaxis of migraine.

Compounds and mixtures prepared by the methods of the present inventionare also useful in the treatment of pain disorders, including forexample fibromyalgia, chronic pain, and neuropathic pain. The term“fibromyalgia” describes several disorders, all characterized by achypain and stiffness in soft tissues, including muscles, tendons, andligaments. Various alternative terms for fibromyalgia disorders havebeen used in the past, including generalized fibromyalgia, primaryfibromyalgia syndrome, secondary fibromyalgia syndrome, localizedfibromyalgia, and myofascial pain syndrome. Previously, these disorderswere collectively called fibrositis or fibromyositis syndromes.Neuropathic pain disorders are thought to be caused by abnormalities inthe nerves, spinal cord, or brain, and include, but are not limited to:burning and tingling sensations, hypersensitivity to touch and cold,phantom limb pain, postherpetic neuralgia, and chronic pain syndrome(including, e.g., reflex sympathetic dystrophy and causalgia).

The magnitude of a prophylactic or therapeutic dose of a compound offormulae A, B or mixtures thereof will vary with the nature and severityof the condition to be treated and the route of administration. Thedose, and perhaps the dose frequency, will also vary according to theage, body weight and response of the individual patient. In general, thetotal daily dose ranges of compounds of the present invention will befrom about 1 mg per day to about 500 mg per day, preferably about 1 mgper day to about 200 mg per day, in single or divided doses. Dosages ofless than 1 mg per day of compounds of the invention are also within thescope of the instant invention.

Any suitable route of administration may be employed. For example, oral,rectal, intranasal, and parenteral (including subcutaneous,intramuscular, and intravenous) routes may be employed. Dosage forms caninclude tablets, troches, dispersions, suspensions, solutions, capsulesand patches.

Pharmaceutical compositions of the present invention include as activeingredient, a single compound, or a mixture of compounds, of formula Aor B, or a pharmaceutically acceptable salt of A or B, together with apharmaceutically acceptable carrier and, optionally, with othertherapeutic ingredients.

The pharmaceutically acceptable carrier may take a wide variety offorms, depending on the route desired for administration, for example,oral or parenteral (including intravenous). In preparing the compositionfor oral dosage form, any of the usual pharmaceutical media may beemployed, such as, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents in the case of oral liquidpreparation, including suspension, elixirs and solutions. Carriers suchas starches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders and disintegrating agents may be used in thecase of oral solid preparations such as powders, capsules and caplets,with the solid oral preparation being preferred over the liquidpreparations. Preferred solid oral preparations are tablets or capsules,because of their ease of administration. If desired, tablets may becoated by standard aqueous or nonaqueous techniques. Oral and parenteralsustained release dosage forms may also be used.

Exemplary formulations, are well known to those skilled in the art, andgeneral methods for preparing them are found in any standard pharmacyschool textbook, for example, Remington, THE SCIENCE AND PRACTICE OFPHARMACY, 21st Ed., Lippincott.

Thus, as set forth herein, the invention is exemplified by the followingaspects and embodiments.

A method for converting an oxime into an enamide. The method includes,(a) contacting the oxime with a phosphine and an acyl donor, underconditions appropriate to convert the oxime into the enamide.

The method according to the preceding paragraph in which the oxime hasthe formula:

wherein R¹, R² and R³ are members independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl. At least two of R¹, R² and R³ are optionally joined toform a ring system selected from substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl.

The method of any of the preceding paragraphs in which the oxime has theformula:

wherein Ar is a member selected from substituted or unsubstituted aryland substituted or unsubstituted heteroaryl. R⁴ is a member selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl; and, the index a is selected from the integers from 1to 4.

The method of any of the preceding paragraphs in which R⁴ is substitutedor unsubstituted aryl.

The method of any of the preceding paragraphs in which R⁴ is substitutedor unsubstituted phenyl.

The method of any of the preceding paragraphs in which R⁴ is phenylsubstituted with at least one halogen.

The method of any of the preceding paragraphs in which R⁴ has theformula:

wherein X¹ and X² are independently selected halo moieties.

The method of any of the preceding paragraphs in which X¹ and X² areeach chloro.

The method of any of the preceding paragraphs in which Ar is substitutedor unsubstituted phenyl.

The method of any of the preceding paragraphs in which the oxime has theformula:

The method of any of the preceding paragraphs in which acyl donor hasthe formula: Z—C(O)—R⁵, wherein Z is a leaving group. R⁵ is a memberselected from H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.

The method according any of the preceding paragraphs in which Z has theformula:

R⁶—C(O)—O—

wherein R⁶ is a member selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl and substituted orunsubstituted heterocycloalkyl.

The method according to any of the preceding paragraphs in which both R⁵and R⁶ are independently selected substituted or unsubstituted C₁-C₄moieties.

The method according to any of the preceding paragraphs in which thephosphine has the formula:

P(Q)₃

wherein each Q is a member independently selected from H, substituted orunsubstituted alkyl and substituted or unsubstituted aryl.

The method according to any of the preceding paragraphs in which each Qis a member independently selected from substituted or unsubstitutedC₁-C₆ alkyl.

The method according to any of the preceding paragraphs in which thecontacting is in solution with an aprotic solvent.

The method according to any of the preceding paragraphs in which theaprotic solvent is an aromatic solvent.

The method according to any of the preceding paragraphs in which theaprotic aromatic solvent is selected from toluene, xylene andcombinations thereof.

The method according to any of the preceding paragraphs in which enamidehas the formula:

The method according to any of the preceding paragraphs in which C-4 hasa configuration selected from R, S and mixtures thereof.

The method according to any of the preceding paragraphs in which C-4 isof S configuration.

The method according to any of the preceding paragraphs furtherincluding: (b) contacting the enamide formed in step (a) with ahydrogenation catalyst and hydrogen or hydrogen transfer reagent underconditions appropriate to hydrogenate a carbon-carbon double bond of theenamide, thereby converting the enamide to an amide.

The method according to any of the preceding paragraphs in which thecatalyst is a chiral catalyst.

The method according to any of the preceding paragraphs in which thechiral catalyst is a complex of a transition metal with a chiralphosphine ligand.

The method according to any of the preceding paragraphs in which theamide is a racemic or chiral amide.

The method according to any of the preceding paragraphs in which amidehas the formula:

The method according to any of the preceding paragraphs in which C-1 andC-4 have a configuration independently selected from R and S.

The method according to any of the preceding paragraphs in which C-1 isof R configuration; and C-4 is of S configuration.

The method according to any of the preceding paragraphs furtherincluding: (c) contacting the amide with a deacylating reagent underconditions appropriate to deacylate —HNC(O)R⁵ of the amide, therebyforming an amine.

The method according to any of the preceding paragraphs including: (d)isolating said amine.

The method according to any of the preceding paragraphs in whichisolating comprises selective crystallization.

The method according to any of the preceding paragraphs in which theamine has the formula:

wherein Q⁻ is an anion; and e is 0 to 1.

The method according to any of the preceding claims in which C-1 and C-4have a configuration independently selected from R and S.

The method according to any preceding claims in which C-1 is of Rconfiguration; and C-4 is of S configuration.

A method of converting an oxime having the formula

into an enamide having the formula:

wherein R⁴ is selected from substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. R⁵ is selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl. The method includes: (a) contacting the oxime with aphosphine and an acyl donor under conditions appropriate to convert theoxime to the enamide.

The method according to the preceding paragraph in which C-4 is of Sconfiguration.

The method according to the preceding paragraphs in which the phosphineis a trialkylphosphine.

The method according to the preceding paragraphs in which the oxime, theacyl donor and the phosphine are dissolved in an aromatic solvent.

The method according to the preceding paragraphs in which the acyl donoris an alkyl anhydride.

The method according to the preceding paragraphs including: (b)contacting the enamide formed in step (a) with a chiral hydrogenationcatalyst and hydrogen under conditions appropriate to hydrogenate acarbon-carbon double bond conjugated to C(O) of the enamide, therebyconverting the enamide to an amide having the formula:

wherein C-1 has a configuration selected from R and S.

The method according to the preceding paragraphs in which the chiralcatalyst includes rhodium complexed to a chiral phosphine ligand.

The method according to the preceding paragraphs further including: (c)contacting the amide with a deacylating reagent under conditionsappropriate to deacylate —HNC(O)R⁵ of the amide, thereby forming anamine having the formula:

wherein Q⁻ is an anion. The index e is 0 or 1.

The method according to the preceding paragraphs in which thedeacylating reagent is an enzyme.

The method according to the preceding paragraphs in which thedeacylating reagent is an acid.

A mixture comprising:

wherein R⁴ is a member selected from substituted or unsubstituted aryland substituted or unsubstituted heteroaryl. Q⁻ is an anion. The indicese and f are independently selected numbers from 0 to 1; and x and y areselected from R and S, such that when x is R, y is R, and when x is S, yis S.

The mixture according to the preceding paragraph in which A is presentin the mixture in a diastereomeric excess of at least 90% relative to B.

The mixture according to the preceding paragraphs in which A is presentin said mixture in a diastereomeric excess of at least 98% relative toB.

The mixture according to the preceding paragraphs in which x and y areR.

The mixture according to the preceding paragraphs in which x and y areS.

The mixture according to the preceding paragraphs in which R⁴ issubstituted or unsubstituted phenyl.

A pharmaceutical formulation including a mixture according to thepreceding paragraphs.

The following examples are provided to illustrate selected embodimentsof the invention and are not to be construed as limiting its scope.

EXAMPLES Example 1 Synthesis ofN—((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1-yl)acetamide (3)1.1. Synthesis of Oxime 2

A suspension formed from a mixture of (S)-tetralone 1 (56.0 g, 0.192mol), hydroxylamine hydrochloride (14.7 g, 0.212 mol), and sodiumacetate (17.4 g, 0.212 mol) in methanol (168 mL) was heated to refluxfor 1 to 5 hours under a N₂ atmosphere. The progress of the reaction wasmonitored by HPLC. After the reaction was complete, the reaction mixturewas concentrated in vacuo. The residue was diluted with toluene (400 mL)and 200 ml water. The organic layer was separated and washed with anadditional 200 mL water. The organic layer was concentrated and dried togive crude solid oxime 2 (58.9 g, 100%), m. p. 117-120° C.

¹H NMR (400 MHz, CDCl₃) δ (ppm) 9.17 (br, 1H, OH), 7.98 (m, 1H), 7.36(d, 1H, J=8.0 Hz), 7.29 (m, 2H), 7.20 (d, 1H, J==2.4 Hz), 6.91 (m, 2H),4.11 (dd, 1H, J=7.2 Hz, 4.4 Hz), 2.82 (m, 2H), 2.21 (m, 1H), 2.08 (m,1H). ¹³C NMR (100 MHz, CDCl₃) δ 154.94, 144.41, 140.40, 132.83, 130.92,130.82, 130.68, 130.64, 129.98, 129.38, 128.12, 127.64, 124.48, 44.52,29.51, 21.27.

1.2. Synthesis of Enamide 3

The solution of the crude oxime 2 (59 g, 0.193 mol) in toluene (500 mL)was purged with N₂ for 30 min. Et₃P (25 g, 0.212 mol) was charged. Afterstirring for 10 min, acetic anhydride (21.6 g, 20 mL, 0.212 mol) wasadded. The reaction mixture was refluxed for 8 to 13 h. Progress of thereaction was monitored by HPLC. The reaction mixture was cooled to roomtemperature. 6N NaOH (aq) (86 mL, 0.516 mol) and 1.0 M (n-Bu)₄NOH inmethanol (1.0 mL) were added. The hydrolysis was complete in about 2 to4 h. The organic layer was separated and diluted with EtOAc (300 mL) and2-BuOH (30 mL). The diluted organic solution was washed with 1% HOAc(aq) solution (300 mL) and DI water (3×300 mL) and concentrated to about350 mL of a slurry in vacuo. The slurry was diluted with heptane (100mL) and 2-BuOH (4 mL) and heated to reflux to form a clear solution.Heptane (50 to 200 mL) was slowly added until a cloudy solution formed.The suspension was slowly cooled to rt. The product was filtered out,washed with 30% toluene and 70% heptane (3×100 mL) solution and dried ina vacuum oven to give 56.9 g white solid (enamide 3, 89% yield), m. p.167-168° C.

(S)-Tetralone 1 (50.0 g, 0.172 mol) was slurried in methanol (150 mL)with hydroxylamine hydrochloride (13.1 g, 0.189 mol) and sodium acetate(15.5 g, 0.189 mol). The resulting suspension was heated to reflux for 2to 6 h under an inert atmosphere with progress monitored by HPLC. Oncompletion, the mixture was cooled to 25° C., diluted with toluene (300mL) and quenched with 1.7 N NaOH (100 mL). The mixture was concentratedin vacuo under reduced pressure, the aqueous layer removed and theorganic layer washed further with DI water (100 mL). Further toluene(300 mL) was charged to the vessel and water removed by azeotropicdistillation. Once at ambient temperature, n-Bu₃P (47.1 mL, 0.183 mol)was charged to the reactor, followed by acetic anhydride (32.5 mL, 0.344mol). The reaction was heated to reflux and monitored by HPLC. After20-24 h, the reaction was cooled to ambient temperature and quenchedwith 6 N NaOH (120 mL). This mixture was allowed to react for 2 to 6 hbefore the aqueous layer was removed. The organic phase was washed withDI water (100 mL). Concentration of the mixture in vacuo, cooling toroom temperature and diluting with isopropanol (50 mL) was done prior toaddition of heptane to assist with crystallization. An initial charge ofheptane (50 mL) was followed by an additional 650 mL. Aging of theslurry followed by filtration, washing (4×100 mL heptane) and dryingyielded a light yellow solid (enamide 3, 44.1 g, 77%).

¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.35 (d, 1H, J=8.4 Hz), 7.26 (m, 3H),7.17 (m, 1H), 7.05 (dd, 1H, J=8.0, 1.6 Hz), 7.00 (br, 1H), 6.87 (m,0.82H, 82% NH rotamer), 6.80 (br, 0.18H, 18% NH rotamer), 6.31 (t,0.82H, 14.8 Hz, 82% H rotamer), 5.91 (br, 0.18H, 18% H rotamer), 4.12(br, 0.18H, 18% H rotamer), 4.03 (t, 0.82H, J=8.0 Hz, 82% H rotamer),2.72 (m, 1H), 2.61 (ddd, 1H, J=16.8, 8.0, 4.8 Hz), 2.17 (s, 2.46H, 82%CH₃ rotamer), 1.95 (s, 0.54H, 18% CH₃ rotamer). 100 MHz ¹³C NMR (CDCl₃)δ 169.3, 143.8, 137.7, 132.3, 131.8, 131.4, 130.5, 130.3, 130.2, 128.8,128.1, 127.8, 127.2, 123.8, 122.5, 121.2, 117.5, 42.6, 30.3, 24.1.

Example 2 Synthesis ofN-((1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide(4)

The enamide 3 (24 g, 72 mmol) was slurried in degassed isopropanol (200mL). The resulting slurry was transferred to the appropriate reactor.Prior to the addition of the catalyst solution, the content of thereactor was purged with nitrogen. A solution of (R,R)-MeBPE(COD)RhBF₄catalyst (20.1 mg, 0.036 mmol, 0.05 mol %) in isopropanol (IPA) (100 mL)was added to the reactor. The content was cooled to 0° C. and purgedwith nitrogen three times. The reactor was then purged with hydrogen andpressurized to 90 prig. The reaction was aged with agitation at 0° C.for 7.5 h and conversion was monitored by the hydrogen uptake. Thecontent was then warmed to RT and hydrogen was vented. After purgingwith nitrogen, the contents were drained. The reaction mixture washeated to 50° C. and filtered through a pad of Celite. The clear orangesolution was concentrated to ˜50% volume (150 mL) and diluted withtoluene (5.9 g, 5 wt %). The suspension was heated to 65° C. and water(14.7 mL) was added dropwise to form a cloudy solution. The slurry wasslowly cooled to −10° C. and aged for 30 minutes. The solid was filteredand washed with cold IPA (2×45 mL). The cake was dried under vacuum at45° C. overnight to afford 20.0 g (83% yield) of trans acetamide 4 (>99%de).

¹H NMR (CDCl₃) 400 MHz δ 7.34 (dd, 2H, J=7.9, 2.4 Hz), 7.23 (t, 1H,J=7.5 Hz), 7.15 (m, 2H), 6.85 (dd, 1H, J=8.2, 2.0 Hz), 6.82 (d, 1H,J=7.7 Hz), 5.72 (d, 1H, J=8.4 Hz), 5.31 (dd, 1H, J=13.2, 8.1 Hz), 4.10(dd, 1H, J=7.0, 5.9 Hz), 2.17 (m, 2H), 2.06 (s, 3H), 1.87 (m, 1H). 1.72(m, 1H); ¹³C NMR (CDCl₃) 100 MHz δ 169.7, 146.9, 138.8, 137.7, 132.6,130.8, 130.6, 130.5, 130.3, 128.4, 128.3, 127.9, 127.4, 47.9, 44.9,30.5, 28.4, 23.8.

Example 3 Synthesis of(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-aminehydrochloride (5)

A solution of trans-acetamide 4 (9.0 g, 26.9 mmol), n-propanol (45 mL)and 5M hydrochloric acid (45 mL) was refluxed for approximately 48 h(90-93° C.). During this time, the reaction temperature was maintainedat ≧90° C. by periodically collecting the distillate until the reactiontemperature was >92° C. Additional n-propanol was added periodically tomaintain the solution at its original volume. After the hydrolysis wascomplete, the solution was slowly cooled to 0° C., resulting in aslurry, which was aged for one hour at 0° C. The reaction mixture wasfiltered, and the cake was washed with 1:1 methanol/water (20 mL),followed by t-butyl methyl ether (20 mL). The wet-cake was dried undervacuum at 45 to 50° C. to afford 7.0 g of the amine hydrochloride 5 (80%yield).

¹H NMR (DMSO-d₆) δ 1.81-1.93 (m, 2H), 2.12-2.21 (m, 1H), 2.28-2.36 (m,1H), 4.28 (t, 1H, J=6.8), 4.59 (br.s, 1H), 6.84 (d, 1H, J=7.6), 7.05(dd, 1H, J=8.4, 1.6), 7.25 (t, 1H, J=7.6), 7.32 (t, 1H, J=7.6), 7.37 (d,1H, J=1.6), 7.56 (d, 1H, J=8.4), 7.76 (d, 1H, J=7.2), 8.80 (br.s, 3H);¹³C NMR (DMSO-d₆) 147.4, 138.9, 133.6, 131.0, 130.5, 130.4, 130.1,129.0, 128.9, 128.4, 128.2, 126.8, 47.9, 43.1, 27.8, 25.2.

Example 4 In Situ Formation/Acylation of Oxime

Oxime 2 was acylated in situ to afford the intermediate 2A, whichundergoes reductive acylation to provide a mixture of the acylatedenamide 3 and the diacylated analog 3A. The reaction was carried out ineither toluene or o-xylene at reflux. The mixture of 3 and 3A was thentreated with an aqueous solution of base such as sodium hydroxide orsodium carbonate, with or without a phase transfer catalyst (e.g.tetrabutylammonium hydrogen sulfate/hydroxide), to convert theintermediate 3A to the desired enamide 3. Exemplary reaction conditionsfor the conversion of oxime 2 to enamide 3 are shown in Schemes 3a and 3b.

Example 5 Catalytic Asymmetric Hydrogenation of the Enamide 3 Using(R,S,R,S)-MePenn Phos(COD)RhBF₄ as the Catalyst

As shown in Scheme 4, the enamide 3 was subjected to homogeneouscatalytic asymmetric hydrogenation in the presence of a chiral catalyst,H₂, and a solvent. In this example the catalyst was derived from thecomplex of the transition metal rhodium with the chiral phosphineligand,(1R,2S,4R,5S)—P,P-1,2-phenylenebis{(2,5-endo-dimethyl)-7-phosphabicyclo[2.2.1]heptane}(R,S,R,S-MePennPhos).The hydrogenations were carried out at a substrate concentration ofabout 0.12 M to about 0.24 M of compound 3.

Example 6 Catalytic Asymmetric Hydrogenation of the Enamide 3 Using(R,R)-MeBPE Rh(COD)BF₄ as the Catalyst

As shown in Scheme 5, the enamide 3 was subjected to homogeneouscatalytic asymmetric hydrogenation in the presence of a chiral catalyst,H₂, and a solvent. In this example the catalyst was derived from thecomplex of the transition metal rhodium with the chiral phosphineligand, (R,R)-1,2-bis(2,5-dimethylphospholano)ethane (R,R-MeBPE). Thehydrogenations were carried out in the concentration range of about 0.12M to about 0.24 M relative to the substrate 3.

Example 7 Asymmetric Hydrogenation Catalyzed by (R,R)-Norphos(COD)RH—BF₄

A slurry of the (S)-enacetamide,N—((S)-4-(3,4-dichloropheyl)-3,4-dihydronaththalen-1-yl)acetamide (60.4g, 0.18 mol), in isopropanol (595.0 g) was purged of oxygen withvacuum/nitrogen cycles. The homogeneous catalyst precursor (referred toas a “catalyst”), (R,R)-Norphos(COD)RH—BF4 was added as a solution inmethanol (34.6 mg, 0.025 mol %, 0.53 mL). After purging the system withhydrogen several times, the vessel was filled with hydrogen at thedesired reaction pressure (approx 7 bar). The mixture was stirred at 25°C. and reaction progress was monitored by hydrogen uptake. Once thereaction was judged to be complete (hydrogen uptake and HPLC), thepressure was released and the system was purged repeatedly withnitrogen. The light yellow slurry was diluted with isopropanol (194.7g), heated to dissolution (65° C.) and polish filtered. The mixture washeated to reflux to dissolve all solids. The solution was slowly cooledto 60-65° C. at which time the product crystallized. The antisolvent,water (262 g), was added at about 60-65° C., then the mixture was cooledto 0° C. over two hours and held at that temperature for aging.Filtration of the lightly colored solid was followed by washing withcold isopropanol (2×61 g). Drying of the off white solid under reducedpressure at 50-55° C. provided the (1R,4S)-acetamide in 99% de (56.6 g,93% yield).

Example 8 Oxime and Enamide Formation

Chiral (4S)-tetralone (100.0 g, 0.34 mol) was reacted with hydroxylaminehydrochloride (28.7 g, 0.41 mol) and sodium acetate (33.8 g, 0.41 mol)in toluene (1.37 L) for approximately 2 h at 103° C. Water was removedfrom the reaction mixture by azeotropic distillation. The reaction wasquencher at 25° C. with 2 N sodium hydroxide (167.0 g). The aqueousphase was separated and the organic phase was washed once with water(400.0 g). Toluene (700.0 g) was added was added and the resultingorganic solution, containing the oxime, was dried by azeotropicdistillation under reduced pressure to the desired reactionconcentration. Triethylphosphine (89.0 g, 0.38 mol, 50 wt % in toluene)is added, followed by addition of acetic anhydride (38.5 g, 0.38 mol),which afforded the oxime acetate intermediate. The reaction mixture wasallowed to react at reflux (112-113° C.) until the remaining oximeacetate is <2% of the product, as determined by HPLC. The reactionmixture was cooled to 20-25° C. and the minor enimide by-product washydrolyzed (to enacetamide) using 6 N sodium hydroxide (210 g) inconjunction with the phase transfer reagent, tertbutylammonium hydroxide(5.0 g). The biphasic mixture was allowed to phase separate and theaqueous phase was discarded. The organic phase was washed with 0.5%acetic acid aqueous solution (67° C., 600.0 g). The aqueous phase wasremoved and the organic phase was washed once with water (67° C., 600.0g) to remove inorganic salts. The organic phase was concentrated and thewarm solution was polish filtered to remove additional inorganic salts.Heptanes (150 g) and 2-butanol (7.0 g) were added and the slurry washeated to 100° C. in order to achieve dissolution. The solution wascooled to approximately 85° C. to initiate crystallization. Additionalheptanes (190 g) were added to the slurry at 85° C., and the mixture wasthen cooled to 0° C. The slurry was aged at 0° C. for 15 min., thenfiltered and washed three times with a solution consisting of a mixtureof heptanes and toluene (125 g). The product was vacuum dried at 35-45°C. 17.8 g (89% yield) of a white crystalline solid, (S)-enacetamide wasrecovered.

The method according to this example was applied to a number ofsubstrates, the results of which are set forth in Table 1.

TABLE 1 Oximes and Enamides Produced Enamide En- reaction try Oxime,yield time Enamide, yield  1

16.5 h

 2

22 h

 3

23 h

 4

19 h

 5

24 h

 6

21.5 h

 7

21.5 h

 8

5.3 h

 9

10 h

10

10 h

11

22.5 h

12

28 h

13

<22 h

Example 9 Amide Deprotection

A solution of (1R,4S)-acetamide in dry THF (212.7 g, 239.3 mL) wastreated with dry pyridine (8.7 g, 8.9 mL, 110 mmol). The resultingclear, colorless solution was cooled to approximately 0° C. Oxalylchloride (12.9 g, 8.9 mL, 101.6 mmol) was added dropwise to the stirredsolution, with care to control the exotherm and effervescence of CO andCO₂. The addition of the activating reagent was accompanied by theformation of a slurry. The slurry was allowed to stir cold for a shortperiod (approx. 15 min) prior to sampling for conversion assessment.Once the reaction was complete, dry propylene glycol was added to thereaction, resulting in a minor exotherm. The reaction was warmed to 25°C., during which time the slurry changed in color and consistency. HPLCanalysis of a second sample showed completion before the addition of1-propanol (96.9 g, 120.5 mL). 6N HCl (128.0 g, 120.0 mL) was added. Themixture was heated to effect dissolution and the resulting mixture waspolish filtered. THF was removed by atmospheric distillation. Afterconcentration of the mixture, it was slowly cooled to 3° C. Theresulting lightly colored slurry was filtered to yield and off-whitecake. The cake was first washed with 17 wt % n-PrOH in deionized water(72.6 g, 75 mL total) and then with cold mtBE (55.5 g, 75 mL). Theoff-white wet cake was dried under vacuum at 45-50° C. The product wasrecovered as an off-white to white solid (24.8 g, 84.1% yield) withexcellent purity (>99% purity by HPLC).

All publications and patent documents cited in this application areincorporated by reference in their entirety for all purposes to the sameextent as if each individual publication or patent document were soindividually denoted. By their citation of various references in thisdocument, Applicants do not admit any particular reference is “priorart” to their invention.

What is claimed:
 1. A method for converting an oxime into an enamide,said method comprising: (a) contacting said oxime with a phosphine andan acyl donor, under conditions appropriate to convert said oxime intosaid enamide.
 2. The method according to claim 1 wherein said oxime hasthe formula:

wherein R¹, R² and R³ are members independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl, and at least two of R¹, R² and R³ are optionallyjoined to form a ring system selected from substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. 3.The method according to claim 1, wherein said oxime has the formula:

wherein Ar is a member selected from substituted or unsubstituted aryland substituted or unsubstituted heteroaryl; R⁴ is a member selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl; and a is selected from the integers from 1 to
 4. 4.The method according to claim 3 wherein R⁴ is substituted orunsubstituted aryl.
 5. The method according to claim 4 wherein R⁴ issubstituted or unsubstituted phenyl.
 6. The method according to claim 5wherein R⁴ is phenyl substituted with at least one halogen.
 7. Themethod according to claim 6 wherein R⁴ has the formula:

wherein X¹ and X² are independently selected halo moieties.
 8. Themethod according to claim 7 wherein X¹ and X² are each chloro.
 9. Themethod according to claim 3 wherein Ar is substituted or unsubstitutedphenyl.
 10. The method according to claim 9, said oxime having theformula:


11. The method according to claim 1 wherein said acyl donor has theformula:Z—C(O)—R⁵ wherein Z is a leaving group; and R⁵ is a member selected fromH, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.
 12. The method according to claim 11 wherein Z has theformula:R⁶—C(O)—O— wherein R⁶ is a member selected from substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl and substituted or unsubstituted heterocycloalkyl.
 13. Themethod according to claim 12 wherein both R⁵ and R⁶ are independentlyselected substituted or unsubstituted C₁-C₄ moieties.
 14. The methodaccording to claim 1 wherein said phosphine has the formula:P(Q)₃ wherein each Q is a member independently selected from H,substituted or unsubstituted alkyl and substituted or unsubstitutedaryl.
 15. The method according to claim 14 wherein each Q is a memberindependently selected from substituted or unsubstituted C₁-C₆ alkyl.16. The method according to claim 1 wherein said contacting is insolution with an aprotic solvent.
 17. The method according to claim 16wherein said aprotic solvent is an aromatic solvent.
 18. The methodaccording to claim 17 wherein said aprotic aromatic solvent is selectedfrom toluene, xylene and combinations thereof.
 19. The method accordingto claim 15 wherein said enamide has the formula:


20. The method according to claim 19 wherein C-4 has a configurationselected from R, S and mixtures thereof.
 21. The method according toclaim 20 wherein C-4 is of S configuration.
 22. The method according toclaim 1, said method further comprising: (b) contacting said enamideformed in step (a) with a hydrogenation catalyst and hydrogen orhydrogen transfer reagent under conditions appropriate to hydrogenate acarbon-carbon double bond of said enamide, thereby converting saidenamide to an amide.
 23. The method according to claim 22 wherein saidcatalyst is a chiral catalyst.
 24. The method according to claim 23wherein said chiral catalyst is a complex of a transition metal with achiral phosphine ligand.
 25. The method according to claim 22 whereinsaid amide is a racemic or chiral amide.
 26. The method according toclaim 22 wherein said amide has the formula:


27. The method according to claim 26 wherein C-1 and C-4 have aconfiguration independently selected from R and S.
 28. The methodaccording to claim 27 wherein C-1 is of R configuration; and C-4 is of Sconfiguration.
 29. The method according to claim 22, further comprising:(c) contacting said amide with a deacylating reagent under conditionsappropriate to deacylate —HNC(O)R⁵ of said amide, thereby forming anamine.
 30. The method according to claim 29, further comprising: (d)isolating said amine.
 31. The method according to claim 30, wherein saidisolating comprises selective crystallization.
 32. The method accordingto claim 29 wherein said amine has the formula:

wherein Q⁻ is an anion; and e is 0 to
 1. 33. The method according toclaim 32 wherein C-1 and C-4 have a configuration independently selectedfrom R and S.
 34. The method according to claim 33 wherein C-1 is of Rconfiguration; and C-4 is of S configuration.
 35. A method of convertingan oxime having the formula

into an enamide having the formula:

wherein R⁴ is selected from substituted or unsubstituted awl andsubstituted or unsubstituted heteroaryl; and R⁵ is selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl, said method comprising: (a) contacting said oxime witha phosphine and an acyl donor under conditions appropriate to convertsaid oxime to said enamide.
 36. The method according to claim 35 whereinC-4 is of S configuration.
 37. The method according to claim 34 whereinsaid phosphine is a trialkylphosphine.
 38. The method according to claim35 wherein said oxime, said acyl donor and said phosphine are dissolvedin an aromatic solvent.
 39. The method according to claim 35 whereinsaid acyl donor is an alkyl anhydride.
 40. The method according to claim35, said method further comprising: (b) contacting said enamide formedin step (a) with a chiral hydrogenation catalyst and hydrogen underconditions appropriate to hydrogenate a carbon-carbon double bondconjugated to C(O) of said enamide, thereby converting said enamide toan amide having the formula:

wherein C-1 has a configuration selected from R and S.
 41. The methodaccording to claim 40 wherein said chiral catalyst comprises rhodiumcomplexed to a chiral phosphine ligand.
 42. The method according toclaim 40, further comprising: (c) contacting said amide with adeacylating reagent under conditions appropriate to deacylate —HNC(O)R⁵of said amide, thereby forming an amine having the formula:

wherein Q⁻ is an anion; and e is 0 or
 1. 43. The method according toclaim 42 wherein said deacylating reagent is an enzyme.
 44. The methodaccording to claim 42 wherein said deacylating reagent is an acid.
 45. Amixture comprising:

wherein R⁴ is a member selected from substituted or unsubstituted aryland substituted or unsubstituted heteroaryl; Q⁻ is an anion; e and f areindependently selected numbers from 0 to 1; and x and y are selectedfrom R and S, such that when x is R, y is R, and when x is S, y is S.46. The mixture according to claim 45 wherein A is present in saidmixture in a diastereomeric excess of at least 90% relative to B. 47.The mixture according to claim 46 wherein A is present in said mixturein a diastereomeric excess of at least 98% relative to B.
 48. Themixture according to claim 45 wherein x and y are R.
 49. The mixtureaccording to claim 45 wherein x and y are S.
 50. The mixture accordingto claim 45 wherein x is S and y is R.
 51. A pharmaceutical formulationcomprising a mixture according to claim 45 and a pharmaceuticallyacceptable carrier.